At Monash University, student enrolments in physiology are large (450-550) with lectures still the primary mode of teaching. Lectures develop students’ physiology knowledge, but not their communication, teamwork or critical thinking skills. The challenge is to modify lectures to encourage student engagement, active learning and the development of communication, teamwork, and critical thinking skills. In a previous study we found that real time digital inking on a Tablet PC in lectures stimulates student interest and understanding of physiology (1). In this study we have added guided-inquiry activities into these lectures. This is based on the constructivist theory of learning and an active learning approach termed POGIL (Process Oriented Guided Inquiry Learning; 3, 5) which has been shown to be effective in lectures, encouraging student participation and enhancing student learning (2, 3). We developed guided-inquiry activities for three physiology lectures: (i) endocrine control of calcium homeostasis, (ii) the oxygen and haemoglobin dissociation curve and (iii) the chemical digestion of foods. During each guided-inquiry lecture, students were initially provided with background information relevant to the lecture concepts. This was followed by a guided-inquiry activity on the concept in which students interpreted graphs, answered questions and solved problems. An interactive discussion about the concepts followed the guided-inquiry activity. To evaluate the effectiveness of the guided-inquiry lecture approach students were given a diagnostic multiple choice question quiz (pre-test) covering the core concepts at the beginning of semester. This quiz was repeated immediately after each lecture (post-test) to measure student learning. The results showed a significant improvement in student performance on the quiz questions between the pre and post tests (P < 0.05). At the end of semester a survey was used to evaluate student perceptions of the guided-inquiry lectures (4; 55 responses). Students found that the guided inquiry lectures (i) encouraged them to take notes during the lecture (82%); (ii) stimulated class questions and/or discussions (91%); (iii) helped them to understand the lecture topics (89%) and (iv) encouraged them to attend lectures (75%). Written comments from students included: “The guided inquiry lectures encouraged discussion with peers and lecturers. I felt that I could ask stupid questions.” In conclusion, we have found that this guided-inquiry approach can be used in large lecture cohorts to motivate active student learning and enhance student understanding of core physiology concepts.